ethyl 4-amino-2-chloropyrimidine-5-carboxylate，4-amino-2-chloro-pyrimidine-5-carboxylic acid ethyl ester

To a stirred solution of (R)-tert-butyl 2-(3-(tert-butoxycarbonyl)piperazin-1-yl)- 7, 8-dihydropyrido[4, 3-d]pyrimidine-6(5H)-carboxylate (12 g, 28.60 mmol, 1.0 equiv) in MeCN (150 mL) was added K2CO3 (7.91 g, 57.20 mmol, 2.0 equiv) and ethyl 4-amino-2- chloropyrimidine-5-carboxylate (6.92 g, 34.32 mmol, 1.2 equiv). The reaction mixture was stirred at 80 C for 12 h, at which point the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (0%17% EtOAc/petroleum ether) afforded the desired product (16 g, 91.6% yield) as a yellow solid. LCMS (ESI) m/z: [M + H] calcd for C28H40N8O6: 585.32; found 585.1.To a solution of (R)-tert-butyl 2-(3-(((tert-butyldiphenylsilyl)oxy)methyl) piperazin-1-yl)-7, 8-dihydropyrido[4, 3-d]pyrimidine-6(5H)-carboxylate (17.2 g, 29.26 mmol, 1.0 equiv) in MeCN (200 mL) was added K2CO3 (12.13 g, 87.78 mmol, 3.0 equiv) and To a solution of (R)-tert-butyl 2-(3-(((tert-butyldiphenylsilyl)oxy)methyl) piperazin-1-yl)-7, 8-dihydropyrido[4, 3-d]pyrimidine-6(5H)-carboxylate (17.2 g, 29.26 mmol, 1.0 equiv) in MeCN (200 mL) was added K2CO3 (12.13 g, 87.78 mmol, 3.0 equiv) and To a solution of tert-butyl 2-(piperazin-1-yl)-7, 8-dihydropyrido[4, 3-d]pyrimidine- 6(5H)-carboxylate (8.3 g, 25.99 mmol, 1.0 equiv) and ethyl 4-amino-2-chloropyrimidine-5- carboxylate (5.24 g, 25.99 mmol, 1.0 equiv) in MeCN (100 mL) was added to K2CO3 (7.18 g, 51.97 mmol, 2.0 equiv). The reaction was stirred at 80 C for 12 h. The reaction was then cooled to room temperature, DCM (100 mL) was added, and the reaction mixture was stirred for 30 min. The suspension was filtered, and the filter cake was washed with DCM (6 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was triturated with EtOAc (30 mL), filtered and then the filter cake was dried under reduced pressure to afford the desired product (8.7 g, 65.9% yield) as light yellow solid.To a solution of tert-butyl 2-(piperazin-1-yl)-7, 8-dihydropyrido[4, 3-d]pyrimidine- 6(5H)-carboxylate (8.3 g, 25.99 mmol, 1.0 equiv) and ethyl 4-amino-2-chloropyrimidine-5- carboxylate (5.24 g, 25.99 mmol, 1.0 equiv) in MeCN (100 mL) was added to K2CO3 (7.18 g, 51.97 mmol, 2.0 equiv). The reaction was stirred at 80 C for 12 h. The reaction was then cooled to room temperature, DCM (100 mL) was added, and the reaction mixture was stirred for 30 min. The suspension was filtered, and the filter cake was washed with DCM (6 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was triturated with EtOAc (30 mL), filtered and then the filter cake was dried under reduced pressure to afford the desired product (8.7 g, 65.9% yield) as light yellow solid.To a solution of tert-butyl-N-tert-butoxycarbonyl-N-((2-(piperazin-1- yl)pyrimidin-5-yl)methyl)carbamate (8.3 g, 21.09 mmol, 1.0 equiv) in MeCN (100 mL) was added To a solution of tert-butyl-N-tert-butoxycarbonyl-N-((2-(piperazin-1- yl)pyrimidin-5-yl)methyl)carbamate (8.3 g, 21.09 mmol, 1.0 equiv) in MeCN (100 mL) was added To a solution of commercially available ethyl 4-amino-2-chloro-pyrimidine-5-carboxylate (500 mg, 2.48 mmol) in 1 , 4-dioxane (10 ml_) was added tributyl(oxazol-2-yl)stannane (779 mI_, 3.72 mmol), Pd(PPh3)4 (287 mg, 0.25 mmol) and copper(l) iodide (118 mg, 0.62 mmol) and the mixture was heated at 100 C for 18 hours. Additional tributyl(oxazol-2- yl)stannane (779 mI_, 3.72 mmol) was added and the mixture heated at 100 C for a further 3 hours and allowed to cool to room temperature. The mixture was partitioned between EtOAc (50 ml_) and 1M KF solution (50 ml_), the organic portion separated and the aqueous further extracted with EtOAc (2 x 25 ml_). The combined organic extracts were washed with H2O (50 ml_), brine, dried over MgSCL and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 3% MeOH in DCM afforded the titled compound as a cream solid. (1418) LC-MS (Method 3B): Rt 1.17 mins; MS m/z 235.1 = [M+H]+ (1419) 1 H NMR (500 MHz, Chloroform-d) d 9.05 (br s, 1 H), 8.10 (br s, 1 H), 7.89 (br s, 1 H), 7.43 (br s, 1 H), 6.16 (br s, 1 H), 4.41 (q, J= 7.1 Hz, 2H), 1.42 (t, J= 7.1 Hz, 3H).To a solution of commercially available ethyl 4-amino-2-chloro-pyrimidine-5-carboxylate (200 mg, 0.99 mmol) and 1 H-pyrazole (135 mg, 1.98 mmol) in DMF (5 ml_) was added CS2CO3 (700 mg, 1.98 mmol) and the mixture was stirred for 3 hours. The resulting mixture was partitioned between EtOAc (25 ml_) and H O (25 ml_), the organic portion separated and the aqueous further extracted with EtOAc (2 x 25 ml_). The combined organic extracts were washed with H O (3 x 25 ml_), brine, dried over MgS04 and the solvent removed in vacuo to afford a solid. The solid was suspended in Et20, collected by filtration and dried to afford the titled compound as a white solid. (1402) LC-MS (Method 3B): Rt 1.36 mins; MS m/z 234.1 = [M+H]+ (1403) 1 H NMR (500 MHz, Chloroform-d) d 8.90 (s, 1 H), 8.57 (dd, J= 2.7, 0.7 Hz, 1 H), 8.08 (br s, 1 H), 7.81 (dd, J= 1.6, 0.7 Hz, 1 H), 6.47 (dd, J= 2.7, 1.6 Hz, 1 H), 6.03 (br s, 1 H), 4.38 (q, J= 7.1 Hz, 2H), 1.41 (t, J= 7.1 Hz, 3H).A solution of commercially available ethyl 4-amino-2-chloro-pyrimidine-5-carboxylate (500 mg, 2.48 mmol) and potassium carbonate (686 mg, 4.96 mmol) in a mixture of 1 , 4-dioxane (10 ml_) and water (2 ml_) was de-gassed via nitrogen sparging for 10 mins. Pd(dppf)Cl2 (1330) CH2CI2 (203 mg, 0.25 mmol) was added followed by commercially available (2- fluorophenyl)boronic acid (521 mg, 3.72 mmol) and placed under an atmosphere of nitrogen. The resulting mixture was stirred at 100 C for 2.75 hours. The mixture was allowed to cool, partitioned between DCM (50 ml_) and water (50 ml_), the layers separated and the aqueous portion further extracted with DCM (50 ml_). The combined organic portions were dried over MgSCU and the solvent removed in vacuo. Purification by column chromatography on silica eluting with a gradient of 10 to 30% EtOAc in petrol afforded the titled compound as a cream solid. (1331) LC-MS (Method 3B): Rt 1.62 mins; MS m/z 262.1 = [M+H]+ (1332) 1 H NMR (500 MHz, Chloroform-d) d 9.03 (s, 1 H), 8.00 (td, J = 7.8, 1.8 Hz, 1 H), 7.89 (s, (1333) 1 H), 7.44 (dddd, J = 8.3, 7.4, 4.9, 1.9 Hz, 1 H), 7.24 (td, J = 7.6, 1.2 Hz, 1 H), 7.17 (ddd, J = 11.2, 8.3, 1.1 Hz, 1 H), 5.78 (s, 1 H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H)

Molecular Weight:201.61
XLogP3:1.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:201.0305042
Monoisotopic Mass:201.0305042
Topological Polar Surface Area:78.1
Heavy Atom Count:13
Complexity:191
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes